Mass Spectrometry Imaging Distinguishes Biliary Toxicants on the Basis of Cellular Distribution

Mass spectrometry imaging (MSI) was used to investigate and provide insights into observed biliary pathology found in dogs and rats after administration of two different compounds. Both compounds were associated with peribiliary inflammatory infiltrates and proliferation of the bile duct epithelium. However, MSI revealed very different spatial distribution profiles for the two compounds: Compound A showed significant accumulation within the bile duct epithelium with a much higher concentration than in the parenchymal hepatocytes, while Compound T exhibited only a slight increase in the bile duct epithelium compared to parenchymal hepatocytes. These findings implicate cholangiocyte uptake and accumulation as a key step in the mechanism of biliary toxicity. In both cases, compounds are shown at the site of toxicity in support of a direct mechanism of toxicity on the biliary epithelium. MSI is a powerful tool for localizing small molecules within tissue sections and improvements in sensitivity have enabled localization down to the cellular level in some cases. MSI was also able to identify biomarker candidates of toxicity by differential analysis of ion profiles comparing treated and control cholangiocytes from tissue sections.